J Toxicol Clin Toxicol. 1988;26(3-4):223-32.
Clonidine interaction in amitriptyline poisoning.

Knudsen K, Ricksten SE, Heath A.

Department of Anesthesia and Intensive Care, University of Gothenburg, Sahlgren's Hospital, Sweden.

The effect of clonidine on amitriptyline-induced cardiotoxicity was investigated in an experimental rat mode. A continuous infusion of amitriptyline (30 mg/kg/h) was given until the animal died, usually within 2 hours. Fifteen minutes after starting the amitriptyline infusion, 50 micrograms/kg of clonidine was given intravenously over five minutes. This led to an increase in blood pressure and left ventricular end-diastolic pressure. There was no significant change in cardiac contractility. Heart rate decreased. These changes can be explained by an increase in afterload due to peripheral vasoconstriction. No signs of reduced sympathetic outflow were seen on the ECG. The peripheral effects of clonidine dominated over the central effects, which may be due to a competitive inhibition of amitriptyline at central noradrenergic sites. An increased afterload pushes the heart towards failure and increases mortality. In this model, clonidine did not reverse amitriptyline-induced cardiovascular toxicity. It may even be potentially harmful if used to treat tricyclic antidepressant poisoning.

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Br J Pharmacol. 1977 Apr;59(4):651-60.
A comparison in rabbit isolated hearts of the dysrhythmogenic potential of amitriptyline, maprotiline and mianserin in relation to their ability to block noradrenaline uptake.

Harper B, Hughes IE.

1. In isolated hearts of rabbits, perfusion with (-)-noradrenaline (0.0059 to 5.9 micronM) resulted in chronotropic and inotropic responses and a shortening of the interval between peak atrial and peak ventricular tensions (the A-V contraction interval). No dysrhythmias developed but at higher concentrations (590 micronM) 2 out of 7 hearts developed dysrhythmias (extrasystoles). 2. Perfusion with the antidepressants amitriptyline or maprotiline (4.8 micronM) or mianserin (28.8 micronM) reduced ventricular force, did not change heart rate and only amitriptyline reduced atrial force and lengthened the A-V contraction interval. At 4.8 micronM mianserin produced only a marginal shortening of the A-V contraction interval. 3. At these concentrations no dysrhythmias developed but at higher concentrations (amitriptyline 8 micronM, maprotiline 8 micronM, mianserin 60 micronM) all the agents produced dysrhythmias involving an interference with atrio-ventricular synchronization. 4. In the presence of mianserin (4.8 micronM) perfusion with noradrenaline (0.0059 to 5.9 micronM) shortened the A-V contraction interval and did not produce dysrhythmias. In the presence of amitriptyline or maprotiline (4.8 micronM) or mianserin (28.8 micronM) the A-V contraction interval generally lengthened and most hearts developed dysrhythmias (usually involving interference with atrio-ventricular synchronization). 5. [3H]-(-)-Noradrenaline uptake in perfused rabbit hearts and in mouse isolated atria or vasa deferentia was inhibited by the antidepressants to a similar extent, amitriptyline being marginally most potent (molar potency taken as 1.0), maprotiline being less potent (1.5) and mianserin least potent (2.0)). 6. It is concluded that of these three antidepressants, mianserin is least cardiotoxic in this preparation and that the ability of these antidepressants to predispose to noradrenaline-induced dysrhythmias is not related to blockade of noradrenaline uptake.

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Arzneimittelforschung. 1978;28(10b):1916-20.
Comparative single-dose kinetics of amitriptyline and its N-oxide in a volunteer.

Breyer-Pfaff U, Ewert M, Wiatr R.

Plasma drug levels and urinary metabolites were measured in a volunteer for 28 h after ingestion of amitriptyline hydrochloride or amitriptyline N-oxide (amitriptylinoxide) equivalent to 100 mg of amitriptyline base. The N-oxide initially produced high plasma levels and 15% of the dose was excreted unchanged within 14 h. From comparison of the metabolite excretions, it can be concluded that about 70% of the dose was reduced at the N-oxide group, while comparison of the areas under the plasma group, while comparison of the areas under the plasma level-time curves for amitriptyline pointed to a 55% reduction to the amine. Less drowsiness was experienced after ingesting the N-oxide, and there was no depressive mood.

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Nippon Yakurigaku Zasshi. 1975 Nov;71(8):789-815.
[Behavior pharmacology of maprotiline, a new antidepressant]

[Article in Japanese]

Ueki S, Fujiwara M, Inoue K, Kataoka Y, Ibii N.

The effect of maprotiline (N-methyl-9, 10-ethanoanthracene-9 (10H)-propylamine) on animal behavior was investigated in mice and rats and compared with those of amitriptyline and imipramine. Maprotiline inhibited reserpine hypothermia in mice and tetrabenazine ptosis in rats, while it potentiated the effects of methamphetamine, L-DOPA and apomorphine in mice, in a similar manner to that of amitriptyline and imipramine. Maprotiline was more potent than anitriptyline and imipramine in antagonizing haloperidol-induced catalepsy as well as in suppressing muricide induced by either olfactory bulbectomy or delta-9-tetrahydrocannabinol in rats. Maprotiline potentiated anesthesia induced by thiopental or ether in mice to a lesser degree than did amitriptyline, and failed to counteract the lethal effect of physostigmine or oxotremorine tremor in mice, indicating that this drug has no central anti-cholinergic effect. Maprotiline markedly inhibited hyperemotionality of the rat with either septal lesions or olfactory bulb ablations, suggesting that it does have a tranquilizing effect. Inhibition of conditioned avoidance response of the rat in the shuttle box and reduction of methamphetamine group toxicity with maprotiline were similar to those with amitriptyline. Maprotiline exaggerated pentetrazol convulsion, decreased muscle tone and impaired coordinated motor activity in mice to a much lesser degree than amitriptyline and imipramine. LD50 of maprotiline was approximately twice that of imipramine and three times that of amitriptyline. These results indicate that maprotiline is a new type of antidepressant, has a low toxicity and shares both potent antidepressant and some tranquilizing effect, without possessing central anticholinergic action.

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Br J Pharmacol. 1979 Feb;65(2):331-8.
The relative toxicity of amitriptyline, imipramine, maprotiline and mianserin in rabbits in vivo.

Hughes IE, Radwan S.

1. Conscious or barbiturate-anaesthetized rabbits were slowly infused intravenously with solutions of amitriptyline, imipramine, maprotiline or mianserin, usually until death occurred. 2. Amitriptyline produced death at the lowest dose, imipramine and maprotiline were intermediate while much higher doses of mianserin were required. 3. Convulsions were induced by the antidepressants in all conscious rabbits and the order of potency of the drugs in producing this effect was amitriptyline greater than or equal to imipramine greater than maprotiline greater than mianserin. 4. All four drugs produced a reduction in heart rate and blood pressure in the anaesthetized rabbits and the order of potency in this respect was amitriptyline greater than imipramine greater than maprotiline greater than mianserin. 5. All four drugs produced significant changes in the ECG compared with control rabbits. The P-R interval was lengthened (potency order amitriptyline greater than imipramine greater than or equal to maprotiline greater than mianserin) and the QRS complex was widened (potency order amitriptyline greater than imipramine greater than or equal to maprotiline greater than mianserin). 7. It is concluded that all four drugs show the toxic effects classically associated with tricyclic antidepressants but the relative toxicity amongst these agents varies considerably and is in the order amitriptyline greater than imipramine greater than maprotiline greater than mianserin.

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Can Anaesth Soc J. 1983 Sep;30(5):501-5.
Analgesic properties of meperidine, amitriptyline and phenelzine in mice.

Lee I, Chalon J, Ramanathan S, Gross S, Turndorf H.

Sixty-three white Swiss Webster mice were divided into seven equal groups. Their tolerance to pain (heat applied to the tail by a test tube containing hot water at a temperature measured by telethermometry) was assessed before and after intraperitoneal injection of (1) physiologic saline; (2) meperidine 14 micrograms X g-1; (3) amitriptyline 6 micrograms X g-1 (4) amitriptyline 12 micrograms X g-1; (5) phenelzine 1.5 micrograms X g-1; (6) phenelzine 3 micrograms X g-1; and (7) amitriptyline 6 micrograms X g-1 plus phenelzine 1.5 micrograms X g-1. All post-injection tests were conducted 45 and 90 minutes after administration, and repeated 24 hours later. No significant difference in pain threshold was noted in any pre-injection test or in any test conducted with physiologic saline. By 90 minutes post-injection, all groups receiving drugs developed increased tolerance to pain. Mice which had received phenelzine plus amitriptyline, or either dose of phenelzine were more tolerant to pain for up to 24 hours than mice which had received physiologic saline. The most marked increases in tolerance to pain were seen with 1.5 micrograms X g-1 and 3 micrograms X g-1 of phenelzine and phenelzine plus amitriptyline. However, phenelzine was more effective and had a longer-lasting effect than either dose of amitriptyline, or meperidine. The combination of phenelzine plus amitriptyline was no more effective than phenelzine alone.

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Drug Metab Dispos. 1977 Mar-Apr;5(2):132-42.
Urinary metabolites of amitriptyline in the dog.

Hucker HB, Balletto AJ, Demetriades J, Arison BH, Zacchei AG.

Dogs excreted approximately 45% of an oral dose of 14C-amitriptyline (30 mg/kg) in the urine in 24 hr. Two new urinary metabolites of the drug were identified as dihydrodiol derivatives of amitriptyline and nortriptyline, respectively. The major metabolite in dog urine was 10-hydroxy amitriptyline, excreted mainly in conjugated form. Other metabolites were characterized as 10-hydroxynortriptyline, amitriptyline N-oxide, and nortriptyline. Together, these metabolites accounted for approximately 47% of the urinary radioactivity.

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